This application claims Foreign Priority under 35 USC xc2xa7119 (a-d) of EPO Application No. 98870167.8 filed Jul. 30, 1998.
1. Field of the Invention
The present invention is related to a new compound and a new method for the prevention and/or the treatment of allergy and/or diseases of allergic origin, particularly immediate hypersensitivity allergy.
2. Description of the Related Art
Immediate hypersensitivity is a form of allergic reaction which develops very quickly, namely within seconds or minutes of exposure of the patient to the causative allergen. This immediate reaction can be followed by a second reaction of delayed onset that can lead to inflammatory changes in the target organ and manifests itself by chronic symptoms such as asthma or atopic dermatitis.
Immediate hypersensitivity is mediated by antibodies belonging mainly, but not exclusively, to the IgE isotype. IgE antibodies bind to specific receptors on cells such as basophils, mastocytes or Langerhans"" cells. Upon allergen exposure, surface-bound IgE transduce a signal into the cell, which is followed by cell activation, which in the case of basophils and mastocytes is accompanied by the release of preformed mediators such as histamine and enzymes, and the synthesis of metabolites of arachidonic acid. These mediators are responsible for the development of allergic signs and symptoms, such as bronchospasm, vasodilatation, hypersecretion of mucus and stimulation of sensory nerve ends resulting in pruritus.
IgE antibodies are produced by B lymphocytes that received appropriate activation signals. Full description of the mechanisms by which IgE antibodies are produced can be found in appropriate reviews (see for instance Vercelli D., Allergy Proc. 14, pp. 413-416 (1993)).
Current treatment of allergic symptoms include allergen avoidance, drug therapy and immunotherapy. Complete avoidance from allergen exposure is the most logical approach, but it remains very difficult, or impossible to achieve in a vast majority of cases. Drug therapy is useful, but alleviates the symptoms without influencing their causes. In addition, drug treatment is usually limited by undesirable side-effects.
Current approaches for immunotherapy are:
1) conventional hyposensitisation which is a treatment consisting in administering to the patient progressively increasing doses of the allergen(s) to which he has developed a sensitivity;
2) allergen alteration aiming at reducing recognition by specific antibodies, IgE in particular;
3) allergen-derived peptides used to interfere in the cognate interaction between specific B and T cells or containing an IgE-binding B cell epitope.
Such allergen-derived peptides containing one or a few T cell epitope(s) used in animal experiments and in human beings in an attempt to inhibit specific T cell activation and induce a state of T cell unresponsiveness, are described in the patent application WO93/08279.
One human application of this concept is the administration of a peptide derived from the sequence of T cell epitopes present on the Fel dI allergen, by subcutaneous injections in cat-sensitive individuals (Wallner B. P., Gefter M. L., Allergy 49, pp. 302-308 (1994)). An alternative, complementary approach of this concept has also been used in animal experiments. The peptides used are modified in such a manner as to keep the ability to bind to MHC-class II determinants on specific B cells, but which have lost their capacity to activate the corresponding T cells (O""Hehir R. E. et al., International Immunology 3, pp. 819-826 (1991)).
It is known that allergic reactions are generated by the liberation of mediators from target cells, such as basophils or mastocytes, having high-affinity surface receptors for IgE, which are occupied by IgE antibodies. The minimum requirement for mediator liberation to occur is that two IgE molecules recognising the same allergen are cross-linked, which in turn cross-link the receptor, resulting in the transduction of an activating signal within the cell. If only one IgE molecule is able to bind the allergen, no cell activation ensues, but the binding site of the IgE would be occupied, preventing cell activation upon exposure to native allergen. The use of a single IGE-binding epitope has therefore been claimed to be a suitable approach for the treatment of allergic diseases (Ball T. et al., J. Biol. Chem. 269, pp. 28323-28328 (1994), EP-A-0714662).
U.S. Pat. No. 4,946,945 describes a protein conjugate useful in immunotherapy, composed of a biological response modifier (BRM) and an allergen. Said conjugate could be combined with a pharmaceutically acceptable carrier. Cytokin, bacterial, fungal and viral immunopotentiators and thymus hormones are disclosed as suitable BRMs for use in said document.
The patent application WO95/31480 describes the preparation and the use of a synthetic compound made of two alpha-helices with specific arrangements of various amino acids. Said compound is used as a support for the binding of functional units, especially epitopes B and/or T.
It is meant by xe2x80x9catopyxe2x80x9d, a predisposition, partly of genetic origin, of an individual having an immune system producing an excess of antibodies belonging to the IgE isotype in response to exposure to allergens. Individuals presenting such characteristics are therefore called xe2x80x9catopicsxe2x80x9d.
An xe2x80x9callergenxe2x80x9d is defined as a substance, usually a macromolecule of proteic composition, which elicits the production of IgE antibodies in predisposed, preferably genetically disposed, individuals (atopics).
Similar definitions are presented in the following references: Clin. Exp. Allergy, No. 26, pp. 494-516 (1996); Mol. Biol. of Allergy and Immunology, ed. R. Bush, Immunology and Allergy Clinics of North American Series (August 1996).
These allergens are preferably the main allergens which are selected from the group consisting of:
food allergens present in peanuts, codfish, egg white, soybean, shrimp, milk and wheat,
house dust mites allergens obtained from Dermatophagoides spp. pteronyssinus, farinae and microceras, Euroglyphus maynei or Blomia,
allergens from insects present in cockroach or hymenoptera,
allergens from pollen, especially pollens of tree, grass and weed,
allergens present in animals, especially in cat, dog, horse and rodent,
allergens present in fungus, especially from Aspergillus, Alternaria or Cladosporium, and
occupational allergens present in such products as latex, amylase, etc.
Said allergens can also be main allergens present in moulds or various drugs such as hormones, antibiotics, enzymes, etc.
xe2x80x9cAllergyxe2x80x9d is the ensemble of signs and symptoms which are observed whenever an atopic individual encounters an allergen to which he has been sensitised, which may result in the development of various diseases and symptoms such as allergic rhinitis, bronchial asthma, atopic dermatitis, etc.
xe2x80x9cHypersensitivityxe2x80x9d is an untoward reaction produced in a susceptible individual upon exposure to an antigen to which he has become sensitised; immediate hypersensitivity depends of the production of IgE antibodies and is therefore equal to allergy.
It is meant by the terms xe2x80x9cepitopexe2x80x9d or xe2x80x9cantigenic determinantxe2x80x9d, one or several portions (which may define a conformational epitope) of an antigen (structure of a macromolecule, including an allergen, preferably made of proteic composition but also made of one or more hapten(s) or portion of a pharmaceutical active compound) which are specifically recognised and bound by an antibody or a receptor at the cell surface of a B or T lymphocyte.
The purpose of the present invention is to provide a vaccination strategy by which the antibody response made by atopic individuals against allergens is deviated from the allergen major determinants that are spontaneously recognised by atopic individuals, to determinants on the same molecule that are spontaneously recognised by antibodies of non-atopic individuals, or to determinants which are not spontaneously recognised by the majority of individuals, independently of their atopic status.
The present invention is related to a compound comprising either
at least one allergen antigenic determinant which is recognised by a B cell or antibody secreted by a B cell of a non-atopic (to said allergen) individual (including cryptic determinant which is not recognised by atopics individuals, and minimally recognised by non-atopics individuals) and which is preferably not recognised by a T cell, and at least one antigenic determinant of an antigen different from said allergen, said antigenic determinant triggering T cell activation, or
a nucleotide sequence encoding said both antigenic determinants, said sequence being possibly linked to one or more regulatory sequence(s) active into a patient""s cell.
The specific allergen antigenic determinants present in known main allergens are easily identified by the person skilled in the art, who may select said epitopes or antigenic determinants of said allergen which are recognised by non-atopic individuals (non-atopic individuals to said allergen) and which may differ from the other epitopes for which atopic individuals produce antibodies as above-described. Similarly, the person skilled in the art may select the specific antigenic determinant of any antigen (different from said allergen) which is known to trigger T cell activation. Preferably, said antigen is not an allergen. A preferred selection of this epitope is described in the examples presented hereafter.
The compound according to the invention will produce in atopic patients a shift of the anti-allergen immune response towards epitopes or antigenic determinants that are not spontaneously or only minimally recognised by antibodies of atopic patients.
In the compound according to the invention, the allergen antigenic determinant and the antigenic determinant of the non-allergic antigen are preferably peptidic sequences chemically bound together (in a linear tandem form or branched form), preferably by a peptidic link, which is preferably made of at least two amino-acids. The compound according to the invention is in a linear or a cyclic form, with or without additional moieties used, for instance to block peptidexe2x80x94peptide interactions.
Advantageously, the allergen is selected from the group consisting of Der pI and Der pII of house dust mite Dermatophagoides pteronyssinus, the major antigen of Aspergillus fumigatus, the staphylococcal B enterotoxin (SEB) and the bovine xcex2-lactoglobulin or the allergen described in the documents Clin. Exp. Allergy, No. 26, pp. 494-516 (1996); Mol. Biol. of Allergy and Immunology, ed. R. Bush, Immunology and Allergy Clinics of North American Series (August 1996).
Advantageously, in the compound according to the invention, the antigenic determinant of an antigen which triggers T cell activation is a T cell epitope (preferably a helper T cell epitope) of tetanus toxoid, diphtheria, mycobacterium, influenza or measles viruses antigens (other examples of said T cell epitopes are described in the table II of the document WO95/26365).
Preferably, the compound according to the invention is selected from the group consisting of the peptides having the following amino acid sequences:
SEQ ID NO. 1:
QYIKANSKFIGITELGGHEIKKVLVPGCHGS
SEQ ID NO. 2:
HEIKKVLVPGCHGS
SEQ ID NO. 3:
DQYIKANSKFIGITELGGQYIKANSKFIGITELSSCHGSEPCIIHRGKPFGGCHGSEPC IIHRGKPFSSCHGSEPCIIHRGKPFGGCHGSEPCIIHRGKPFSSCHGSEPCIIHRGKPF GGCHGSEPCIIHRGKPFSR
SEQ ID NO. 4:
PKYVKQNTLKLATGKKGPKYVKQNTLKLATGKKGVIIGIK
SEQ ID NO. 5:
QYIKANSKFIGITELGGCHGSEPCNIHRGKPF
or a nucleotidic sequence encoding at least one of said amino-acids sequences, preferably the nucleotide sequence
SEQ ID NO. 6: GAATTCCCACCATGGATCAGTATATAAAAGCAAATTCTAAATTT ATAGGTATAACTGAACTAGGAGGTTGCCATGGTTCAGAACCATGTATCATTCATCGTGG TAAACCATTCGGCGGTTGTCACGGAAGTGAGCCTTGCATTATACACAGAGGAAAGCCGT TCTAAGCGGCCGC.
Another aspect of the present invention is related to a pharmaceutical, cosmetical, food and/or feed composition comprising the compound according to the invention and a pharmaceutical, cosmetical, food and/or feed acceptable carrier.
Preferably, said pharmaceutical composition is a vaccine which may comprise a pharmaceutical acceptable carrier which can be any compatible non-toxic substance suitable for administering the composition (vaccine) according to the invention to a patient and obtain the desired therapeutical or prophylactic properties. The pharmaceutically acceptable carrier according to the invention suitable for oral administration are the ones well known by the person skilled in the art, such as tablets, coated or non-coated pills, capsules, solutions or syrups. Other adequate pharmaceutical carriers or vehicles may vary according to the mode of administration (cutaneous, epicutaneous, subcutaneous, intradermal, inhalation, patching, intravenous, intramuscular, parenteral, oral, etc.).
When the compound according to the invention is a nucleotidic sequence, the compound according to the invention can be administered naked or on a suitable pharmaceutical carrier such as a xe2x80x9cvectorxe2x80x9d used for the transfection, transduction and expression of said sequence by a cell of the patient (including the expression and secretion outside the cell of the peptidic sequence encoded by said nucleotic sequence). Said xe2x80x9cvectorxe2x80x9d is preferably selected from the group consisting of plasmids, viruses (retroviruses, adenoviruses, . . . ), lipidic vectors (such as cationic vesicles, liposomes, . . . ), molecules or devices which result in a chemical or a physical modification of the transfected cell (dextran phosphate, calcium phosphate, micro-injection device, electroporation device, etc.) or modified recombinant organisms comprising the compound according to the invention derived for instance from Salmonella or Mycobacteria strains, a nucleic acid encapsulated in the form of micro- or nanoparticles such as chirosan as described by Roy et al., Nature Medicine 5, pp. 387-391 (1999), etc.
The genetic modification of the patient""s cell(s) for an ex vivo or in vivo treatment can be obtained by the person skilled in the art according to the known methods in the field of genetic therapy (such as the one described in the documents WO91/02805, WO91/18088, WO91/15501).
The pharmaceutical composition or the vaccine according to the invention may also comprise adjuvants (including helper viruses) well known by the person skilled in the art which may modulate the humoral, local, mucosal and/or cellular response of the immune system of a patient and improve the use of the compound according to the invention.
Adjuvants can be of different forms, provided they are suitable for administration to human beings. Examples of such adjuvants are oil emulsions of mineral or vegetal origin; mineral compounds such as aluminium phosphate or hydroxide, or calcium phosphate; bacterial products and derivatives, such as P40 (derived from the cell wall of Corynebacterium granulosum), monophosphoryl lipid A (MPL, derivative of LPS) and muramyl peptide derivatives and conjugates thereof (derivatives from mycobacterium components), alum, incomplete Freund""s adjuvant, liposyn, saponin, squalene, etc. Recent reviews on adjuvants for human administration are described by Gupta R. K. et al. (Vaccine 11, pp. 293-306 (1993)) and by Johnson A. G. (Clin. Microbiol. Rev. 7, pp. 277-289 (1994)).
The pharmaceutical composition according to the invention is prepared by the methods generally applied by the person skilled in the art, for the preparation of various pharmaceutical compositions, especially vaccines, wherein the percentage of the active compound/pharmaceutically acceptable carrier can vary within very large ranges (generally a suitable dosage unit form contains about 0.005 xcexcg to about 1 mg of compound per kg/body weight of patient), only limited by the tolerance and the level of accointance of the patient to the compound. The limits are particularly determined by the frequency of administration and by the specific diseases or symptoms to be treated.
Preferably, the compound is present in the pharmaceutical composition in a concentration which allows at least the reduction or suppression of the signs and symptoms of allergy or of a disease of allergic origin (preferably signs and symptoms of immediate hypersensitivity allergy).
The cosmetical composition according to the invention may comprise any cosmetical acceptable carrier selected according to the specific mode of administration. For instance, for skin hygiene, the cosmetical composition could be a product in the form of a cream, an ointment or a balsam.
The food or feed composition according to the invention could be any food, feed or beverage acceptable carrier comprising the usual liquid food or feed ingredients wherein the compound according to the invention is included.
Another aspect of the present invention is related to the use of the compound according to the invention as a medicament.
The present invention is also related to the use of the compound according to the invention or the pharmaceutical composition according to the invention for the manufacture of a medicament in the prevention and/or the treatment of allergy or of a disease of allergic origin, particularly immediate hypersensitivity allergy.
Another aspect of the present invention is related to a prevention and/or treatment method of allergy or of a disease of allergic origin, particularly immediate hypersensitivity allergy, comprising the step of administering the compound or the pharmaceutical composition according to the invention to a patient preferably a human patient, especially an atopic individual to an allergen, in order to elicit or increase advantageously the production of antibodies towards antigenic determinants of the allergen that are not spontaneously or only minimally recognised by the immune system of atopic individuals.
These diseases include rhinitis and sinusitis of allergic origin, bronchial asthma, atopic dermatitis, some forms of acute and chronic urticaria, gastro-intestinal syndromes associated with the ingestion of food allergens such as xcex2-lactoglobulin, the so-called oro-pharyngeal syndrome of the same origin, anaphylactic reactions associated with drug hypersensitivity.